Overview of tacrolimus-based immunosuppression after heart or lung transplantation.

Transplantation has evolved into an accepted treatment for end-stage heart or lung disease. Acute rejection, complications related to immunosuppressive protocols, and the development of chronic rejection continue to challenge the long-term success of heart and lung transplantations. Wide acceptance of tacrolimus as an important immunosuppressant in renal and hepatic transplantations has led subsequently to its investigation as primary immunosuppression in heart and lung transplant recipients, either combined with azathioprine or with the newer agents mycophenolate mofetil or rapamycin. Studies have shown that tacrolimus is an effective therapeutic alternative to cyclosporine for primary immunosuppression in heart or lung transplantation and demonstrates equivalent if not improved prophylaxis of acute rejection, and more recently demonstrates a potential influence on chronic rejection, particularly in lung transplant recipients. Of importance, the enhanced immunosuppressive activity of tacrolimus is achieved without increased risk of infection or malignancy. Differences in tolerability profiles and side effects between tacrolimus and cyclosporine may be used in selecting the optimal immunotherapy after thoracic transplantation. In particular, the lesser propensity of tacrolimus to cause hypertension and hyperlipidemia potentially offers decreased cardiovascular risk for heart and lung transplant recipients.     

Calcineurin inhibitor sparing in renal transplantation

Although calcineurin inhibitors (CNIs) are effective at preventing acute rejection, their long-term use is associated with nephrotoxicity that may compromise long-term renal allograft survival. Consequently, there is considerable interest in identifying immunosuppressive regimens that permit reduced exposure to CNIs while maintaining adequate immunosuppression. Introducing such strategies early after transplantation may mean that the development of CNI-associated nephrotoxicity could be minimized or prevented. Several CNI-sparing regimens have shown at least comparable efficacy with standard-dose CNI regimens. In particular, a regimen of mycophenolate mofetil (MMF), corticosteroids, interleukin-2 receptor antagonist induction, and low-dose tacrolimus from the time of transplantation provided superior renal function and a lower acute rejection rate than the same regimen but with low-dose cyclosporine or low-dose sirolimus, or standard-dose cyclosporine, MMF, and corticosteroids. The use of low-dose cyclosporine does not seem to eliminate nephrotoxicity in de novo renal transplant recipients. The early withdrawal of CNIs from MMF-based regimens generally improves renal function but has been associated with an increased risk of acute rejection, in particular when the levels of mycophenolic acid were not adjusted to maintain the same total level of immunosuppression. Research aiming to achieve the "best" balance of efficacy and toxicity of available immunosuppressive regimens continues.     

Is acute rejection the key predictor for long-term outcomes after renal transplantation when comparing calcineurin inhibitors?

In the context of modern immunosuppressive regimens, the overall incidence of acute rejection may no longer be the most accurate surrogate marker for long-term kidney graft survival. The type, severity, timing, and clinical course of acute rejection each influence the impact of a rejection episode, and if renal function recovers fully, there appears to be no survival disadvantage. Randomized clinical trials in renal transplant patients have generally shown that there are fewer acute rejection episodes with tacrolimus compared with cyclosporine, although with contemporary regimens, including mycophenolate acid, this difference is less marked than previously. In randomized trials, kidney graft survival rates with cyclosporine and tacrolimus have proven similar. Large-scale registry analyses have consistently shown no graft survival benefit with tacrolimus vs cyclosporine, and indeed, 2 such analyses have reported significantly higher graft survival with cyclosporine-based immunosuppression compared with tacrolimus in living-donor kidney transplant patients receiving mycophenolate mofetil. There are no reports of improved patient survival with either calcineurin inhibitor after kidney transplantation. In conclusion, the perception of better efficacy with tacrolimus vs cyclosporine based on the incidence of acute rejection is not supported by a difference in graft or patient survival after kidney transplantation.     

Incidence of polyomavirus-nephropathy in renal allografts: influence of modern immunosuppressive drugs.

BACKGROUND: In recent years an increasing number of cases with polyomavirus (PV)-nephropathy after renal transplantation were reported from several transplant centres. New, highly potent immunosuppressive drugs like tacrolimus or mycophenolate mofetil were accused as risk factors for this increase. However, data about the incidence of PV-nephropathy in correlation to different immunosuppressive therapy concepts are lacking. METHODS: All renal transplant biopsies performed at Hannover Medical School between 1999 and 2001 (n=1276) were immunohistochemically screened for the presence of PV-specific proteins. The results were correlated to the different immunosuppressive therapy protocols and patients with PV-nephropathy were compared with a matched control group. RESULTS: PV-nephropathy was found in <1% of all investigated allograft biopsies (11/1276) and in approximately 1% of all patients (7/638), respectively. All patients being immunohistochemically positive for PV-specific proteins also showed the typical morphological changes of PV-nephropathy. Four out of seven patients with PV-nephropathy were under triple immunosuppression comprising tacrolimus and mycophenolate mofetil. Under this immunosuppressive therapy protocol an eight times higher incidence and a 13 times higher risk (multivariate odds ratio 12.7) of PV-nephropathy was observed in our patients compared with the control group. CONCLUSIONS: PV-nephropathy is a rare but serious complication after renal transplantation. A small group of patients under intensive immunosuppression comprising tacrolimus in combination with mycophenolate mofetil has a significantly increased risk of acquiring this deleterious complication.     

Comparative study of cyclosporine and tacrolimus vs newer immunosuppressants mycophenolate mofetil and rapamycin on coronary endothelial function.

BACKGROUND: Endothelial dysfunction contributes to the development of intimal hyperplasia in transplanted hearts by decreasing the protective effects of endothelial-derived nitric oxide. Immunosuppressive drugs may increase the dysfunction caused by rejection and further accelerate the development of graft coronary vasculopathy. This study compares the effect of cyclosporine and tacrolimus vs two newer immunosuppressive drugs, mycophenolate mofetil and rapamycin, on coronary endothelial function. METHODS: An in vitro model of drug incubation in Krebs-bicarbonate solution (4(o)C, 48 hours) using porcine epicardial coronary arteries was developed. Coronary endothelial function studies were performed in organ chamber experiments after incubation with cyclosporine (10(-4), 10(-7) mol/liter), tacrolimus (10(-4), 10(-7) mol/liter), mycophenolate mofetil (10(-4), 10(-7) mol/liter), rapamycin (10(-7), 10(-11) mol/liter), and their vehicles to assess effects on G-protein-mediated vasorelaxations leading to the release of nitric oxide. RESULTS: Exposure to cyclosporine and mycophenolate mofetil was associated with a dose-dependent decrease in endothelium-dependent relaxations to serotonin (an agonist that binds to 5-HT1D receptors coupled to Gi-protein) but no impairment of relaxations to bradykinin (an agonist that binds to B2 receptors coupled to Gq-proteins). Exposure to tacrolimus and rapamycin caused severe impairment of relaxations to serotonin and a lesser one to bradykinin. We observed alterations of relaxations to the calcium ionophore A23187 after exposure to mycophenolate mofetil and rapamycin. Exposure to rapamycin and mycophenolate mofetil vehicles impaired relaxation to all agonists. CONCLUSIONS: These results suggest that cyclosporine and mycophenolate mofetil induce a dysfunction of the vasorelaxing properties of the endothelium that may lead to a decrease in the protective effects of nitric oxide on the vascular wall but that these drugs still have a more favorable vascular profile than do tacrolimus and rapamycin. Decreased endothelial function after mycophenolate mofetil and rapamycin exposure could be caused by their vehicles.     

Drug insight: maintenance immunosuppression in kidney transplant recipients

Kidney transplantation is the treatment of choice for patients with end-stage renal disease, in part because of ongoing efforts towards improving immunosuppressive strategies. Although calcineurin inhibitors remain the mainstay of immunosuppression in kidney transplant recipients, within this class of drug there has been a shift from use of ciclosporin to use of tacrolimus. Mycophenolate mofetil and mycophenolate sodium are now the antimetabolites of choice. A new class of drugs (inhibitors of mammalian target of rapamycin) that includes sirolimus is being increasingly used in stable kidney transplant recipients. New data, however, indicate that a more cautious approach to the use of this drug is warranted. Many transplant centers are now using steroid avoidance, minimization and withdrawal protocols. The impact of these different drugs and therapeutic strategies on outcomes has to be weighed against their immunosuppressive benefit. As more and more community-based nephrologists and primary care physicians are becoming involved in the care of stable kidney transplant recipients, it is important for these clinicians to familiarize themselves with novel immunosuppressive drugs and their pharmacokinetic properties.     

HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies

BACKGROUND: New immunosuppressive drugs such as anti-interleukin-2 receptor antibodies (aIL2R) and mycophenolate mofetil (MMF) have reduced the incidence of acute rejection after renal transplantation. Whether matching donor and recipient human leukocyte antigen (HLA) antigens is still relevant in patients receiving modern immunosuppression has been questioned. METHODS: We retrospectively analyzed the incidence and risk factors of acute rejection during the first posttransplant year and the impact of acute rejection on long-term graft survival in a cohort of 208 renal transplant patients treated with aIL2R (basiliximab, n=166; daclizumab, n=42), calcineurin inhibitors (tacrolimus, n=180; cyclosporin, n=28), mycophenolate mofetil, and steroids. Graft and patient survival were calculated by the Kaplan-Meier method. Risk factors for acute rejection were analyzed by logistic regression modeling. RESULTS: Twenty-seven patients were treated for acute rejection (26 biopsy-proven) during the first posttransplant year. The Kaplan-Meier estimate of first-year acute rejection was 13.2%. The number of HLA mismatches (odds ratio [OR] 1.65 per HLA mismatch) and long periods of dialysis before transplantation (OR 3.1 for more than 4 years of dialysis) were the only independent risk factors for first-year acute rejection. First-year acute rejection was associated with a significant reduction in overall and death-censored graft survival at 5 years after transplantation. CONCLUSIONS: Although infrequent in patients receiving modern immunosuppressive drugs, acute rejection remains an important risk factor for graft loss after renal transplantation. Our results suggest that better HLA matching and shorter periods of dialysis before transplantation could reduce acute rejection rates and further improve outcomes under current immunosuppressive regimens.     

Effect of basiliximab on renal allograft rejection within 1 year after transplantation

Basiliximab is widely used in clinical practice for initial immunosuppressive treatment of renal transplant recipients, seeking to reduce the incidence of acute rejection episodes without adverse events. This retrospective study included 123 renal allograft recipients transplanted at a single center. All were followed for longer than 1 year after transplantation and treated with calcineurin inhibitor and steroid (methylprednisolone) for prophylactic immunosuppression, but basiliximab and mycophenolate mofetil were optional. We compared the outcomes of renal transplant recipients who were versus treated were not with basiliximab as initial immunosuppressive therapy. Basiliximab was used for initial immunosuppression in 42 patients. Their maintenance immunosuppressive treatment included triple (n = 44) or double (n = 79) regimens, including a calcineurin inhibitor (cyclosporine [n = 87] or tacrolimus [n = 36]), methylprednisolone with or without mycophenolate mofetil. Twenty-six (21.1%) patients had a rejection episode within 1 year after transplantation and 22 (17.9%) had infections. Within the first year after transplantation the patients who were treated with basiliximab showed fewer rejection episodes (n = 6, 14.3%) than the patients without this therapy (n = 20, 24.7%), which was not statistically significant (P = .245). However, basiliximab significantly affected the occurrence of rejection episodes among the double immunosuppressive regimen group (P = .006), but not the triple regimen group (P = .098) without an impact on infection episodes (P value of double, triple = .291, .414) within 1 year after transplantation. We concluded that basiliximab was more useful for the recipients treated with double immunosuppression with a calcineurin inhibitor and steroid than for those on a triple regimen including mycophenolate mofetil.     

Liver transplantation and pregnancy

Patients with liver failure have menstrual cycle irregularities or amenorrhea. Liver transplantation restores menstrual pattern among women with cirrhosis in childbearing years. It is now accepted that a planned pregnancy is possible among liver transplant recipients at least 1 year after liver transplantation, with stable allograft function and under immunosuppressive regimens, to minimize the risks of preterm delivery and pregnancy-induced hypertension. After 1 year, the risk of graft loss decreases and is not related to pregnancy. It is a high-risk pregnancy which requires a specific and regular multidisciplinary joint follow-up (obstetrician, hepatologist, and anaesthesiologist), which leads in most cases to successful outcome for mother and child. But, early prevention and multidisciplinary management of the most common complications (pregnancy-induced hypertension, preeclampsia, and fetal growth restriction) is essential. The prematurity rate, maternal morbidity and mortality are higher than in the general population. Usual immunosuppressive treatments (corticoids, cyclosporine, tacrolimus, azathioprine or mycophenolate mofetil) may require dose adaptation during pregnancy. Immunosuppressive drugs are not teratogenic, but breast feeding is not allowed.     

Improvement of drug-induced chronic renal failure in lung transplantation.

BACKGROUND: Nephrotoxicity is a frequently encountered adverse effect of calcineurin inhibitors (cyclosporine and tacrolimus)-combined immunosuppressive regimens. METHODS: We have compared the glomerular filtration rate in 14 patients who underwent lung transplantation, before and after replacement of azathioprine by mycophenolate mofetil and reduction of associated calcineurin inhibitors doses. RESULTS: After a mean follow-up of 16+/-4 months with the modified immunosuppressive regimen, the mean glomerular filtration rate increased by 20% with no change in lung function. CONCLUSION: By its strong immunosuppressive effect, mycophenolate mofetil allows the decrease of associated calcineurin inhibitor doses, with subsequent improvement of renal function without jeopardizing the transplanted lung.     

Cutaneous Toxicities From Transplantation‐Related Medications

Despite the abundance of information on cutaneous malignancies associated with solid organ transplantation in the transplant literature, there is limited information regarding nonmalignant skin changes after transplantation. There are numerous skin toxicities secondary to immunosuppressive and other transplant‐related medications that can vary in presentation, severity, and prognosis. To limit associated morbidity and mortality, solid organ transplant recipient care providers should effectively identify and manage cutaneous manifestations secondary to drug toxicity. Toxicities from the following transplant‐related medications will be discussed: antithymocyte globulins, systemic steroids, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, mammalian target of rapamycin inhibitors sirolimus and everolimus, basiliximab and daclizumab, belatacept, and voriconazole.     

Tacrolimus-induced alopecia in female kidney-pancreas transplant recipients

BACKGROUND: Immunosuppressive drugs given to solid organ transplant recipients may be responsible for cosmetic side effects which can endanger patient compliance. Cyclosporine is associated with hirsutism whereas tacrolimus has been associated with rare cases of alopecia. Since 1998, we have included tacrolimus within the immunosuppressive regimen following kidney-pancreas transplantation. The aim of this study was to evaluate the incidence of alopecia in this population and possible risk factors. METHODS: Between January 1, 1995 and October 31, 2003, 59 consecutive simultaneous kidney-pancreas (SPK) transplants were performed in 58 recipients (27 females and 31 males). The immunosuppressive regimen comprised corticosteroids, calcineurin inhibitor (cyclosporine, n=11; or tacrolimus, n=40) and a purine inhibitor (azathioprine or mycophenolate mofetil). RESULTS: Clinically significant alopecia occurred in 13 patients (28.9%) receiving tacrolimus versus none receiving cyclosporine (P<0.001). Of those who experienced alopecia, 11 were female and two were male (P=0.02). The mean delay between transplantation and alopecia was 422 days (range 100-1,567). Other causes of alopecia were excluded. Treatment of alopecia with topic minoxidil was successful in all cases but one, which required conversion from tacrolimus to cyclosporine. CONCLUSIONS: Alopecia is a frequent complication in women receiving tacrolimus therapy following SPK transplantation. Its pathogenesis is unknown. This cosmetic complication must be discussed with patients before transplantation to minimize the risk of noncompliance.     

Trends in maintenance immunosuppressive drugs used in taiwanese kidney transplant recipients: an analysis of the national health insurance research database

Trends in maintenance immunosuppressive drugs used among Taiwanese kidney transplant recipients have not been reported before. We examined the National Health Insurance Research Database to analyze trends in maintenance immunosuppressive drugs used in Taiwanese kidney transplant recipients for the years 2002-2009. The new case number of kidney transplant recipients ranged from 302 to 673 per year. In 2009, 5276 kidney transplant recipients received immunosuppressive therapy. The 5-year renal graft survival rate of kidney transplant recipients was 93%. In 2009, the most common immunosuppressive therapy among Taiwanese kidney transplant recipients was a triple regimen that included tacrolimus, mycophenolate mofetil, and corticosteroid. There was a significant increase in the use of a tacrolimus-based regimen from 35.1%-58.2%, while the use of cyclosporine decreased from 62.2%-24.8% (P < .05). The percentage of calcineurin inhibitor-free regimen increased from 2.7%-17%. Moreover, the use of Rapamune dramatically increased from 8.2%-22.6% in 2002-2004. However, the percentage of kidney transplant recipients using Rapamune maintained 23 ± 1.6% in 2004-2009. The use of mycophenolic acid remained stable at about 74.9 ± 3.2% in 2002-2009. As predicted, the use of Imuran decreased from 6.9%-3.5%. In summary, although calcineurin inhibitors remained the mainstay of immunosuppressive drugs, these findings suggest a general trends toward individualized regimens and the use of calcineurin inhibitor-free and mammalian target of rapamycin inhibitors-based regimens in Taiwanese kidney transplant recipients.     

Mycophenolate mofetil inhibits intimal hyperplasia and attenuates the expression of genes favouring smooth muscle cell proliferation and migration

AIM: Intimal hyperplasia remains the leading cause of late graft failure following heart transplantation. The immunosuppressive drug mycophenolate mofetil has been shown to inhibit the development of intimal hyperplasia. This study aimed to assess the efficacy of a combination of mycophenolate mofetil, calcineurin inhibition, and sirolimus on the development of intimal hyperplasia. METHODS: Male Sprague-Dawley rats received mycophenolate mofetil (30 mg/kg per day) and either tacrolimus (0.1 mg/kg per day), cyclosporine (5 mg/kg per day), or sirolimus (0.05 mg/kg per day) and were compared to an untreated control group. All animals underwent left common carotid artery balloon angioplasty. Morphometric analysis was performed on representative transverse sections, and intima medial ratios calculated at 2 weeks. Profibrotic gene expression was assessed with competitive RT-PCR at 2 weeks for metalloproteinase-2, metalloproteinase-9, TIMP-1, collagen III, and TGF-beta. Sections were stained with sirius red, and extracellular matrix deposition was quantified. RESULTS: Mycophenolate mofetil in combination with rapamycin was associated with the greatest reduction in intimal thickening (intima medial ratio 0.79; range 0.45-0.86), compared to its combination with either cyclosporine (1.41; range 1.06-1.68, P < .02) or tacrolimus (0.93; range 0.81-1.37, P < .05) and controls (1.47; range 1.02-2.04, P < .005). Mycophenolate mofetil and rapamycin significantly inhibited all profibrotic genes studied compared to controls (P < .01) but there were no differences between tacrolimus and cyclosporine. Mycophenolate mofetil and sirolimus significantly attenuated extracellular matrix deposition compared to tacrolimus and cyclosporin (P < .023). CONCLUSION: The benefits of mycophenolate mofetil in combination with sirolimus are preferential over those with cyclosporine or tacrolimus. Randomised trials are warranted to assess if mycophenolate mofetil should be an alternative agent to calcineurin-inhibitors when used in combination with sirolimus.     

Ambulatory blood pressure monitoring in children after renal transplantation

Arterial hypertension is a common complication in children after renal transplantation and the control of hypertension is often difficult. This retrospective investigates the prevalence and rate of control of hypertension using ambulatory blood pressure monitoring (ABPM) in 45 children (mean age 14.1 +/- 4.3 years, mean time after renal transplantation 2.2 +/- 2.7 years), all on cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil plus daily steroids. The overall prevalence of hypertension was 82%. None of the transplanted children had normal blood pressure without antihypertensive therapy (ie, spontaneous normotension). Twenty percent of children had untreated hypertension, 18% had controlled hypertension, and 62% had uncontrolled hypertension. Prevalence of the nondipping phenomenon was 53%. The mean number of antihypertensive drugs (without diuretic monotherapy) in treated patients was 1.9 drugs per patient. The prevalence of arterial hypertension in children after renal transplantation is high and the control of hypertension is often unsatisfactorily low.     

Clinical consequences of non adherence to immunosuppressive medication in kidney transplant patients

Little is known of the long-term clinical effects of non adherence on transplanted kidneys, especially regarding newer immunosuppressive regimens. In a study of 356 adult Swiss kidney transplant patients, non adherence was measured at inclusion by means of self-reporting, electronic monitoring, collateral reporting and blood assay. Long-term clinical outcomes regarding graft loss and creatinine levels were collected prospectively over a period of 5 years. A Cox proportional hazards model and mixed regression analysis were used, respectively, to examine the effects of non adherence on kidney survival and kidney function. The majority of patients (62%) were on immunosuppressive regimens that included mycophenolate mofetil, tacrolimus or sirolimus. No associations were found between non adherence and kidney graft survival or graft function. Notwithstanding weaknesses of this study, this negative result suggests that high adherence may protect patients against detrimental clinical outcomes, and/or that immunosuppressive regimens containing newer drugs allow wider non adherence margins than those based on previous generation medications such as cyclosporine, azathioprine and corticosteroids.     

Immunosuppressive treatment

Immunosuppressive treatment following renal transplantation includes induction therapy during the initial period when the risk of rejection is higher. Depleting anti-lymphocyte antibodies are indicated mostly in patients who developped anti-HLA antibodies and following a second graft. Anti-IL2 receptor antibodies may be used in non-responders. After the first month, maintenance therapy mostly consists in the association of several immunosuppressants, mainly corticosteroids, an antimetabolic agent (azathioprine or mycophenolate mofetil) and a calcineurin inhibitor (cyclosporine or tacrolimus). Side effects associated with these treatments led to the development of new immunosuppressive protocols, with the reduction or withdrawal of corticosteroids treatment due to its deleterious effects on statural growth, and decreased doses of anti-calcineurin agents to reduce their nephrotoxic effect. These therapeutic options are possible in patients at low immunological risk.     

A short overview on mycophenolic acid pharmacology and pharmacokinetics

Immunosuppressive therapy is used in solid organ transplant treatment, and mycophenolic acid (MPA) is one of the immunosuppressive drugs most used worldwide. It is a potent, selective, non-competitive, and reversible inosine monophosphate dehydrogenase (IMPDH) inhibitor that acts to inhibit guanine synthesis. To improve solubility, MPA is used as the prodrug mycophenolate mofetil (MMF) or as an enteric-coated mycophenolate sodium salt (EC-MPS). It is metabolized into mycophenolic acid phenyl glucuronide (MPAG), the inactive and major metabolite, and into acyl glucuronide (AcMPAG), pharmacologically active. In kidney transplantation, combined immunosuppressive therapy with cyclosporine (CsA) and tacrolimus (Tac) is widely used, showing beneficial effects. This paper aimed to review papers published in the last two decades and discuss factors that can interfere with the pharmacokinetics of MPA. Data collected confirm that MPA plasma levels should be monitored to evaluate immunosuppressive therapy since pharmacokinetics can be influenced by factors such as interpatient variability, coadministration of other immunosuppressive agents, post-transplant period, renal function, and dose. However, to perform drug monitoring, costs and facility may be limitations. Monitoring MPAG together with MPA would be a great improvement in therapy as it represents a big part of MPA levels and can be related to the increase of adverse effects.     

Lung transplants with tacrolimus and mycophenolate mofetil: a review

Traditionally, immunosuppressive maintenance therapy in solid organ transplantation has consisted of cyclosporine (CsA), azathioprine, and prednisone. However, lung transplant recipients are far more frequently affected by acute rejection, especially during the first 6 months after the transplantation, than patients with other transplanted organs. Further, they display a greater risk for chronic transplant dysfunction and ultimate graft loss. Bronchiolitis obliterans syndrome (BOS) is the major cause of morbidity and mortality among long-term survivors after lung transplantation. Acute pulmonary allograft rejection has been identified as the major risk factor for the development of BOS. Based on favourable results in kidney, liver, and heart transplantation, tacrolimus and mycophenolate mofetil have been used as primary prophylaxis and as rescue therapy for recurrent or persistent acute rejection and BOS. A secondary indication is CsA toxicity. This review focuses on reported results of the combination of tacrolimus and mycophenolate mofetil in lung transplantation. These new immunosuppressive drugs have markedly improved the efficacy profiles without additional detrimental toxicities, and appear to be a safe alternative to CsA and azathioprine in patients following lung transplantation. However, at present, BOS is not influenced by these new drugs. The optimal long-term immunosuppressive regimen remains to be established.     

Multicenter Randomized Prospective Trial of Steroid Withdrawal in Renal Transplant Recipients Receiving Basiliximab, Cyclosporine Microemulsion and Mycophenolate Mofetil

Corticosteroids withdrawal from immunosuppressive regimens has thus far been associated with increased risk of acute rejection episodes. In this study, basiliximab, a chimeric monoclonal interleukin-2 receptor antagonist, added to a maintenance regimen consisting of cyclosporine microemulsion and mycophenolate mofetil was studied for its effectiveness in allowing early corticosteroid withdrawal in de novo renal allograft recipients. Primary renal transplant recipients receiving basiliximab, cyclosporine-microemulsion, and mycophenolate mofetil, were randomized to either corticosteroid withdrawal at day four post-transplantation (n = 40) or standard steroid therapy (n = 43). The primary endpoint was the incidence of biopsy-proven acute rejection episodes. Randomized subjects who underwent transplantation and received at least one dose of basiliximab were analyzed in an intent-to-treat fashion. The incidence of biopsy-proven acute rejection at 12 months was not significantly different between the steroid withdrawal group (20%) and the standard treatment group (16%). Patient and graft survival was 100% in the steroid withdrawal group while one death in a patient with a functioning graft occurred in the standard steroid group. Seventy-two percent of the steroid withdrawal group remained off steroids at 6 months post-transplant. Allograft function and incidence of adverse events and infections were similar between the two groups. Rapid and early corticosteroid withdrawal among renal transplant recipients receiving basiliximab induction and daily therapy with cyclosporine-microemulsion and mycophenolate mofetil was not associated with an increased risk of acute rejection.